Background: Ulcerative colitis (UC) is a chronic inflammatory disease caused by abnormal immune system reactions resulting in inflammation and ulcers in the large intestine. Phillygenin (PHI) is a natural compound found in Forsythia suspensa (Thunb.) Vahl, known for its various bioactivities, including anti-inflammatory, anti-obesity, and antipyretic activities. However, the potential anti-inflammatory effects of PHI on UC and its underlying mechanisms are still poorly understood. Methods: In this study, we investigated the therapeutic effects of PHI on acute UC induced by DSS and TNBS. We evaluated the effects of PHI on disease activity index, body weight, mortality, intestinal mucosal barrier, cytokine secretion, and macrophage infiltration into colon tissue using various techniques such as flow cytometry, immunofluorescence, ELISA, RT-qPCR, and Western blotting. Results: Our findings revealed that PHI has therapeutic properties in UC treatment. PHI was able to maintain body weight, reduce disease activity index and mortality, restore the intestinal mucosal barrier, and inhibit cytokine secretion. Flow cytometry assay and immunofluorescence indicated that PHI reduces macrophage infiltration into colon tissue. Additionally, both in vivo and in vitro results suggested that PHI may exert anti-inflammatory effects by downregulating the TLR4/MyD88/NF-κB pathway, inhibiting NLRP3 inflammasome activation. Conclusion: In conclusion, PHI possesses anti-inflammatory properties and has the potential as a therapeutic agent for the treatment of UC. Our study provides insights into the underlying mechanisms of PHI’s therapeutic effects and highlights the potential for further research in developing PHI-based treatments for UC.

Background and Purpose: Pharmacological intervention to induce white adipose tissue browning provides a promising anti-obese therapy. The fruits of Garcinia cambogia (Clusiaceae) have been widely applied to manage body weight. The current study aims to uncover the chemical principles responsible for the anti-obese property of the fruits of G. cambogia and investigate the underlying mechanisms. Experimental Approach: The bioactivity-based molecular networking and Oil-red O staining on 3T3-L1 and C3H10T1/2 adipocytes were applied for guided isolation. High-fat diet-induced obese mice were recruited to evaluate the anti-obese activity. Key Results: Guided by the bioactivity-based molecular networking, several polycyclic polyprenylated acylphloroglucinols were targetedly isolated from the fruits of G. cambogia with lipid lowering effect on adipocytes, including guttiferone J (GOJ), garcinol and 14-deoxygarcinol. As the most potent one, GOJ (10 µM) reduced lipid accumulation by 70% and 76% in 3T3-L1 and C3H10T1/2 adipocytes, respectively. Furthermore, GOJ (2.5‒10 µM) activated the deacetylase Sirtuin 3 (SIRT3), which, in turn, reduced the acetylation level of PPARγ coactivator-1α to boost mitochondrial biogenesis, and promoted uncoupling protein 1 expression and function to enhance thermogenesis, resulting in browning of adipocytes. In high-fat diet-induced-obese mice, GOJ (10 and 20 mg∙Kg-1) protected against adiposity, hyperlipidemia, insulin resistance and liver lipotoxicity, through boosting SIRT3-mediated browning of inguinal white adipose tissue. Conclusions and Implications: The bioactivity-based molecular networking is a promising strategy for guided isolation of bioactive molecules, and GOJ represents a new scaffold of thermogenic inducer, which might be responsible for the anti-obese property of G. cambogia.